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1.
Curr Issues Mol Biol ; 46(8): 8969-8980, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39194747

RESUMEN

Low-grade body inflammation is a major cause of osteoarthritis (OA), a common joint disease. Gut dysbiosis may lead to systemic inflammation which can be prevented by probiotic administration. The Lactobacillus delbrueckii subsp. lactis 557 (LDL557) has been demonstrated to have beneficial effects for anti-inflammation. This study investigated the effects of LDL557 on OA progress using monosodium iodoacetate (MIA)-induced OA of rats. Live or heat-killed (HK)-LDL557 of a low or high dose was administrated for two weeks before MIA-induced OA, and then continuously administrated for another six weeks. After taking supplements for eight weeks, OA progress was analyzed. Results showed that MIA induced knee joint swelling, chondrocyte damage, and cartilage degradation, and supplementation with a high dose of LDL557 reduced MIA-induced knee joint swelling, chondrocyte damage, and cartilage degradation. Additionally, MIA increased serum levels of the matrix-degrading enzyme MMP-13, while a high dose of HK-LDL557 decreased it for the controls. Simultaneously, bone turnover markers and inflammatory cytokines of serum were assayed, but no significant differences were found except for a TNF-α decrease from a low dose of live LDL557. These results demonstrated that supplementation with high doses of live LDL557 or HK-LDL557 can reduce the progression of MIA-induced OA in rats.

2.
Nutrients ; 16(14)2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39064807

RESUMEN

Osteoarthritis (OA) is a chronic degenerative disease leading to articular cartilage destruction. Menopausal and postmenopausal women are susceptible to both OA and osteoporosis. S-equol, a soy isoflavone-derived molecule, is known to reduce osteoporosis in estrogen-deficient mice, but its role in OA remains unknown. This study aimed to explore the effect of S-equol on different degrees of menopausal OA in female Sprague-Dawley (SD) rats induced by estrogen deficiency caused by bilateral ovariectomy (OVX) combined with intra-articular injection of mono-iodoacetate (MIA). Knee joint histopathological change; serum biomarkers of bone turnover, including N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX-I) and N-terminal telopeptide of type I collagen (NTX-I); the cartilage degradation biomarkers hyaluronic acid (HA) and N-terminal propeptide of type II procollagen (PIINP); and the matrix-degrading enzymes matrix metalloproteinases (MMP)-1, MMP-3 and MMP-13, as well as the oxidative stress-inducing molecules nitric oxide (NO) and hydrogen peroxide (H2O2), were assessed for evaluation of OA progression after S-equol supplementation for 8 weeks. The results showed that OVX without or with MIA injection induced various severity levels of menopausal OA by increasing pathological damage, oxidative stress, and cartilage matrix degradation to various degrees. Moreover, S-equol supplementation could significantly reduce these increased biomarkers in different severity levels of OA. This indicates that S-equol can lessen menopausal OA progression by reducing oxidative stress and the matrix-degrading enzymes involved in cartilage degradation.


Asunto(s)
Cartílago Articular , Equol , Menopausia , Ovariectomía , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Estrés Oxidativo/efectos de los fármacos , Femenino , Menopausia/efectos de los fármacos , Ratas , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Equol/farmacología , Biomarcadores/sangre , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Modelos Animales de Enfermedad , Óxido Nítrico/metabolismo
3.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38473759

RESUMEN

Osteoarthritis (OA) causes joint pain and disability due to the abnormal production of inflammatory cytokines and reactive oxygen species (ROS) in chondrocytes, leading to cell death and cartilage matrix destruction. Selenium (Se) intake can protect cells against oxidative damage. It is still unknown whether Se supplementation is beneficial for OA. This study investigated the effects of Se on sodium iodoacetate (MIA)-imitated OA progress in human chondrocyte cell line (SW1353 cells) and rats. The results showed that 0.3 µM of Se treatment could protect SW1353 cells from MIA-induced damage by the Nrf2 pathway by promoting the gene expression of glutathione-synthesis-related enzymes such as the glutamate-cysteine ligase catalytic subunit, the glutamate-cysteine ligase modifier subunit, and glutathione synthetase. In addition, glutathione, superoxide dismutase, glutathione peroxidase, and glutathione reductase expressions are also elevated to eliminate excessive ROS production. Moreover, Se could downregulate NF-κB, leading to a decrease in cytokines, matrix proteases, and glycosaminoglycans. In the rats, MIA-induced cartilage loss was lessened after 2 weeks of Se supplementation by oral gavage; meanwhile, glutathione synthesis was increased, and the expressions of pro-inflammatory cytokines were decreased. These results suggest that Se intake is beneficial for OA due to its effects of decreasing cartilage loss by enhancing antioxidant capacity and reducing inflammation.


Asunto(s)
Cartílago Articular , Osteoartritis , Selenio , Humanos , Ratas , Animales , FN-kappa B/metabolismo , Condrocitos/metabolismo , Selenio/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Glutamato-Cisteína Ligasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Osteoartritis/metabolismo , Estrés Oxidativo , Citocinas/metabolismo , Glutatión/metabolismo , Cartílago Articular/metabolismo
4.
Food Chem ; 445: 138757, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38367563

RESUMEN

Peanut is an important food that can cause food allergies, often leading to moderate and severe allergic symptoms such as skin rashes, asthma, and even anaphylactic shock.Research indicates that Ara h 3 is one of the major peanut allergen. In order to establish a simple analytical method for detecting Ara h 3, we developed a sandwich enzyme-linked immunosorbent assay (ELISA) with antibodies that were induced from purified Ara h 3. The experimental results showed that the purified Ara h 3 had good purity, and we successfully prepared capture and detection antibodies. The method established in this study exhibited high specificity and did not cross-react with soybeans, cashew nuts, and sesame. For validation, including precision, recovery and sensitivity were in good condition. We also detected the Ara h 3 in peanut related foods. Overall, the ELISA developed in this study is a reliable method for Ara h 3 detection.


Asunto(s)
Arachis , Hipersensibilidad al Cacahuete , Antígenos de Plantas , Anticuerpos Monoclonales , Alérgenos , Ensayo de Inmunoadsorción Enzimática/métodos , Hipersensibilidad al Cacahuete/diagnóstico , Proteínas de Plantas/análisis , Albuminas 2S de Plantas
5.
Cartilage ; 13(1): 19476035221077404, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35139660

RESUMEN

OBJECTIVE: The aim of this study is to evaluate the efficacy of intra-articular injection with HYAJOINT Plus, a biofermentation-derived, high-molecular hyaluronic acid (HA), on the progression of structural changes of cartilage in patients with knee osteoarthritis (OA) by using objectively promised ultrasonography (US) evaluation. DESIGN: In this prospective clinical trial, 56 OA patients completed the study. One single dose of injection of HYAJOINT Plus into the knee cavity was performed. The primary efficacy outcome measure for structural change of knee joint was evaluated by US using a semiquantitative grading system. Secondary efficacy outcome measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and subscale scores. All efficacy outcomes were measured at baseline and at first, third, and sixth month following treatment. RESULTS: There were significant US grade-improvement changes of cartilage between baseline and follow-up visits over medial femoral condyle and transverse overall evaluation at 3- and 6-month follow-ups, and over lateral femoral condyle, intercondylar notch, and medial longitudinal area at 6-month follow-up. The improved score change of WOMAC from baseline was significant at 1- and 3-month follow-ups in pain subscale, whereas score change from baseline was significant at 6-month follow-up in total score and all 3 subscale scores. CONCLUSIONS: It was determined that significant improvement was found on cartilage by US after intra-articular injection with high-molecular weight, biological fermentation-derived HYAJOINT Plus. The semiquantitative grading system by US is a promising tool to identify the efficacy on cartilage band after interventions.


Asunto(s)
Ácido Hialurónico , Osteoartritis de la Rodilla , Humanos , Inyecciones Intraarticulares , Articulación de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/tratamiento farmacológico , Resultado del Tratamiento
6.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-34209006

RESUMEN

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.


Asunto(s)
Condrocitos/citología , Equol/farmacología , Nitroprusiato/efectos adversos , Osteoartritis/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Modelos Biológicos , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas
7.
Life (Basel) ; 11(6)2021 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-34070830

RESUMEN

A keloid is a fibroproliferative skin tumor. Proliferating keloid fibroblasts (KFs) demand active metabolic utilization. The contributing roles of glycolysis and glucose metabolism in keloid fibroproliferation remain unclear. This study aims to determine the regulation of glycolysis and glucose metabolism by glucose transporter-1 (GLUT-1), an essential protein to initiate cellular glucose uptake, in keloids and in KFs. Tissues of keloids and healthy skin were explanted for KFs and normal fibroblasts (NFs), respectively. GLUT-1 expression was measured by immunofluorescence, RT-PCR, and immunoblotting. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with or without WZB117, a GLUT-1 inhibitor. Reactive oxygen species (ROS) were assayed by MitoSOX immunostaining. The result showed that glycolysis (ECAR) was enhanced in KFs, whereas OCR was not. GLUT-1 expression was selectively increased in KFs. Consistently, GLUT-1 expression was increased in keloid tissue. Treatment with WZB117 abolished the enhanced ECAR, including glycolysis and glycolytic capacity, in KFs. ROS levels were increased in KFs compared to those in NFs. GLUT-1 inhibition suppressed not only the ROS levels but also the cell proliferation in KFs. In summary, the GLUT-1-dependent glycolysis and ROS production mediated fibroblast proliferation in keloids. GLUT1 might be a potential target for metabolic reprogramming to treat keloids.

8.
Sci Rep ; 11(1): 9390, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33931723

RESUMEN

Keloid is a skin disease characterized by exaggerated scar formation, excessive fibroblast proliferation, and excessive collagen deposition. Cancers commonly arise from a fibrotic microenvironment; e.g., hepatoma arises from liver cirrhosis, and oral cancers arise from submucosal fibrosis. As keloids are a prototypic fibroproliferative disease, this study investigated whether patients with keloids have an increased cancer risk. In a matched, population-based study, first 17,401 patients treated for keloids during 1998-2010 with 69,604 controls without keloids at a ratio of 1:4 were evaluated. The association between keloids and risk of cancer was estimated by logistic regression or Cox proportional hazard regression models after adjustment of covariates. In total, 893 first-time cases of cancer were identified in the 17,401 patients with keloids. The overall cancer risk was 1.49-fold higher in the keloids group compared to controls. Regarding specific cancers, the keloids group, had a significantly higher risk of skin cancer compared to controls (Relative risk = 1.73). The relative risk for skin cancer was even higher for males with keloids (Relative risk = 2.16). Further stratified analyses also revealed a significantly higher risk of developing pancreatic cancer in female patients with keloids compared to controls (Relative risk = 2.19) after adjustment for known pancreatic cancer risk factors. This study indicates that patients with keloids have a higher than normal risk for several cancer types, especially skin cancers (both genders) and pancreatic cancer (females). Therefore, patients with keloids should undergo regular skin examinations, and females with keloids should regularly undergo abdominal ultrasonography.


Asunto(s)
Queloide/complicaciones , Neoplasias/patología , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/etiología , Pronóstico , Estudios Retrospectivos , Taiwán/epidemiología , Adulto Joven
9.
Adv Wound Care (New Rochelle) ; 9(9): 491-501, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32941122

RESUMEN

Objective: Keloid is an abnormal scar that often develops in high-tension skin. It is caused by excessive fibroblast proliferation and collagen deposition. Nonmuscle myosin IIA (NM-IIA) is an important motor protein that regulates the mechanical transduction of cells. However, the role of NM-IIA in keloid pathogenesis remains unclear. Approach: NM-IIA expression was examined and compared in keloid skin and normal skin by immunofluorescence. The organization of smooth muscle actin (SMA)-mediated stress fibers in normal and keloid fibroblasts (NFs and KFs, respectively) were determined. Cell proliferation and cell contractility were measured in fibroblasts derived from normal and keloids. The NM-II pharmacological inhibitor (blebbistatin) and RNA interference were applied to block NM-IIA and investigate its regulatory role in SMA-mediated stress fibers, cell contractility, and cell proliferation after NM-IIA inhibition. Results: NM-IIA expression is increased in keloid tissue. Inhibition of NM-II by blebbistatin or targeting NM-IIA by RNA interference reduced transforming growth factor beta (TGF-ß)-mediated SMA-mediated stress fiber formation, cell proliferation, and cell contractility of NFs and KFs. Although TGF-ß failed to mediate phosphorylation of myosin light chain (pMLC, the activator of NM-II), pMLC can interact with SMA-mediated stress fiber. Finally, inhibition of NM-II by blebbistatin also reduced NF and KF proliferation after TGF-ß stimulation. Innovation: NM-IIA synergizes with TGF-ß to regulate fibroblast proliferation, contraction activity, and myofibroblasts differentiation. Conclusion: NM-IIA might be one of the therapeutic targets in keloids.


Asunto(s)
Diferenciación Celular/genética , Proliferación Celular/genética , Queloide/metabolismo , Miofibroblastos/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Células Cultivadas , Colágeno/metabolismo , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Queloide/patología , Masculino , Persona de Mediana Edad , Miofibroblastos/citología , Miosina Tipo IIA no Muscular/antagonistas & inhibidores , Miosina Tipo IIA no Muscular/genética , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Piel/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
10.
Biochem Biophys Res Commun ; 521(1): 50-56, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31610916

RESUMEN

Osteoarthritis (OA) is characterized with articular cartilage degradation, and monosodium iodoacetate (MIA)-treated chondrocyte is the most commonly used model for mimicking OA progression. Zinc protects chondrocytes from MIA-induced damage. Here, we explored the protective effects of 25 µM zinc on 5 µM MIA-treated SW1353 cells (human chondrosarcoma cell line) through the analysis of energy metabolism- and autophagy-related parameters. We found that the exposure of SW1353 cells to MIA decreased ATP levels, expression of glycolysis-related proteins, including glucose transporter 1, hexokinase 2, and pyruvate dehydrogenase E1 component subunit alpha, and the levels of mitochondrial complex I, II, IV, and V subunits of the oxidative phosphorylation pathway. MIA treatment also decreased the expression of autophagy-related proteins, including autophagic elongation protein 5 (ATG5), ATG7, and microtubule-associated protein 1A/1B light chain 3B (LC3-II) and mitophagy-related proteins, including phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), ubiquitin, and p62. These results indicate that MIA interferes with energy metabolism and the autophagic clearance of dysfunctional mitochondria (so called mitophagy). Interestingly, zinc exposure could almost completely reverse the effects of MIA, suggesting its potential protective role against OA progression.


Asunto(s)
Adenosina Trifosfato/metabolismo , Condrocitos/efectos de los fármacos , Ácido Yodoacético/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Mitofagia/efectos de los fármacos , Sustancias Protectoras/farmacología , Sulfato de Zinc/farmacología , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ácido Yodoacético/farmacología , Mitocondrias/metabolismo , Células Tumorales Cultivadas
11.
Toxicol In Vitro ; 53: 57-66, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30026126

RESUMEN

Arsenic is known to perturb epidermal homeostasis and induce abnormal keratinocyte proliferation, leading to skin carcinogenesis. P63 and its isoforms are essential to regulate epidermal homeostasis. This study aimed to investigate the role of p63 isoforms in abnormal epidermal proliferation induced by arsenic. Using arsenic-induced Bowen's disease (As-BD; an intraepidermal carcinoma) as a disease model, we found that in As-BD, the expression of proliferating basal keratinocytes marker cytokeratin 14 (CK14) and N-terminal truncated p63 isoform (ΔNp63; proliferation regulator) was increased, however, that of the differentiation marker cytokeratin 10 (CK10) and full-length p63 isoform (TAp63; differentiation regulator) was decreased in squamous cells as compared with healthy subjects. These observations were recapitulated in the arsenic-treated skin equivalents (SEs). The SEs showed that arsenic increased epidermal thickness, induced abnormal proliferation, and increased ΔNp63 expression in squamous cells as compared with the control. Treatment of cultured normal human epidermal keratinocytes (HKCs) with arsenic increased CK14 and △Np63 expressions, but decreased TAp63 and CK10 expressions. Furthermore, knockdown of ΔNp63 by RNA interference abrogated arsenic-induced CK14 expression and recovered the reduction of TAp63 and CK10 caused by arsenic. These findings indicated that ΔNp63 is a pivotal regulator in the abnormal cell proliferation in arsenical cancers.


Asunto(s)
Intoxicación por Arsénico , Enfermedad de Bowen , Epidermis/efectos de los fármacos , Neoplasias Cutáneas , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Bowen/inducido químicamente , Enfermedad de Bowen/metabolismo , Enfermedad de Bowen/patología , Proliferación Celular , Células Cultivadas , Epidermis/metabolismo , Epidermis/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Adulto Joven
12.
Nutrients ; 10(4)2018 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-29641501

RESUMEN

Osteoarthritis (OA) is an age-related degenerative joint disease characterized by high oxidative stress, chondrocyte death and cartilage damage. Zinc has been implicated in the antioxidant capacity of the cell, and its deficiency might inhibit chondrocyte proliferation. The present study examined the potential of zinc as a preventive supplement against OA using the in vitro chondrosarcoma cell line SW1353 and an in vivo Wistar rat model to mimic OA progress induced by monosodium iodoacetate (MIA). The results demonstrated that, in SW1353 cells, 5 µM MIA exposure increased oxidative stress and decreased the expression of GPx1 and Mn-SOD but still increased GSH levels and HO-1 expression and enhanced the expression of interleukin (IL)-10, IL-1ß, and matrix metalloproteinase (MMP)-13. Zinc addition could block these changes. Besides, the expression of Nrf2 and phosphorylated (p)-Akt was dramatically increased, implicating the p-Akt/Nrf2 pathway in the effects of zinc on MIA-treated cells. A rat model achieved similar results as those of cell culture, and 1.6 mg/kg/day of zinc supplementation is sufficient to prevent OA progress, while 8.0 mg/kg/day of zinc supplementation does not have a better effect. These findings indicate that zinc supplementation exerts a preventive effect with respect to MIA-induced OA progress.


Asunto(s)
Antioxidantes/farmacología , Cartílago Articular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Interleucinas/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/prevención & control , Sulfato de Zinc/farmacología , Animales , Antioxidantes/metabolismo , Cartílago Articular/enzimología , Cartílago Articular/patología , Línea Celular Tumoral , Condrocitos/enzimología , Condrocitos/patología , Citoprotección , Hemo-Oxigenasa 1/metabolismo , Humanos , Masculino , Osteoartritis/enzimología , Osteoartritis/patología , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos
13.
Apoptosis ; 23(3-4): 226-236, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29468482

RESUMEN

Epirubicin is an anthracycline and is widely used in tumor treatment, but has toxic and undesirable side effects on wide range of cells and hematopoietic stem cells (HSC). Osteoblasts play important roles in bone development and in supporting HSC differentiation and maturation. It remains unknown whether epirubicin-induced bone loss and hematological toxicity are associated with its effect on osteoblasts. In primary osteoblast cell cultures, epirubicin inhibited cell growth and decreased mineralization. Moreover, epirubicin arrested osteoblasts in the G2/M phase, and this arrest was followed by apoptosis in which both the extrinsic (death receptor-mediated) and intrinsic (mitochondrial-mediated) apoptotic pathways were evoked. The factors involved in the extrinsic apoptotic pathway were increased FasL and FADD as well as activated caspase-8. Those involved in the intrinsic apoptotic pathway were decreased Bcl-2; increased reactive oxygen species, Bax, cytochrome c; and activated caspase-9 and caspase-3. These results demonstrate that epirubicin induced osteoblast apoptosis through the extrinsic and intrinsic apoptotic pathways, leading to the destruction of osteoblasts and consequent lessening of their functions in maintaining bone density and supporting hematopoietic stem cell differentiation and maturation.


Asunto(s)
Apoptosis/efectos de los fármacos , Epirrubicina/farmacología , Mitocondrias/efectos de los fármacos , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Caspasas/genética , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Citocromos c/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Osteoblastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
14.
J Cancer ; 8(16): 3173-3182, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29158789

RESUMEN

Background: Cancer cells proliferate rapidly and are resistant to cell death, relying on aggravated glycolysis to satisfy their increased demand for energy and biosynthetic precursors. However, this process may create unfavorable microenvironments, such as increased acidity, leading to cytotoxicity. Our previous study demonstrated that arecoline induces anoikis of HA22T/VGH hepatoma cells. The present study aimed to examine if arecoline induced anoikis is related to the glycolytic pathway and explore the underlying mechanisms. Methods: HA22T/VGH cells were treated with arecoline and changes in the glycolytic end products lactate and ATP, glycolytic-related gene expression, intracellular and extracellular pH, pH-regulating gene expression, reactive oxygen species (ROS) levels, intracellular Ca2+ concentration ([Ca2+]i) and mitochondrial membrane potential were examined, relative to untreated cells. Cell viability and morphology were also assessed. Results: Arecoline increased lactate and ATP production through induction of glycolytic genes, including glucose transporter 3 (Glut3), hexokinase 1 (HK1), hexokinase 2 (HK2), and pyruvate kinase (PK). The intracellular pH was not changed, despite increased lactate levels, implying that intracellular H+ was exported out of the cells. mRNA expression of pH regulators including monocarboxylate transporter 1 and 4 (MCT 1 and 4), sodium bicarbonate cotransporter 1 (NBC1), carbonic anhydrases (CA) IX and XII and vacuolar ATPase (V-ATPase) were down-regulated. Na+/H+ exchanger 1 (NHE1) mRNA levels remained unchanged while Na+/Ca2+ exchanger (NCX) was up-regulated and eventually [Ca2+]i was increased. ROS generation was increased and mitochondrial membrane potential was decreased followed by cell detachment and death. Addition of 2-deoxy-d-glucose, a glucose competitor that interferes with glycolysis, attenuated arecoline induction of lactate [Ca2+]i, ROS and cell detachment. Similarly, ROS scavengers could block the effects of arecoline. Conclusions: This study demonstrated that arecoline induced glycolysis and modulated the mRNA expression of pH-regulator genes in HA22T/VGH cells. This phenomenon led to the elevation of [Ca2+]i, ROS generation, and subsequent cell detachment.

15.
Int J Mol Sci ; 18(1)2016 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-28035982

RESUMEN

Osteoarthritis (OA) is the most prevalent joint disease. Dietary intake of vitamin C relates to a reduction in cartilage loss and OA. This study examined the efficacy of vitamin C to prevent OA with the in vitro chondrosarcoma cell line (SW1353) and the in vivo monosodium iodoacetate (MIA)-induced OA rat. Results demonstrated that, in SW1353 cells, treatment with 5 µM MIA inhibited cell growth and increased oxidative stress, apoptosis, and proteoglycan loss. In addition, the expression levels of the pro-inflammatory cytokines IL-6, IL-17A, and TNF-α and matrix metalloproteinases (MMPs) MMP-1, MMP-3, and MMP-13 were increased. All of these MIA-induced changes could be prevented with treatment of 100 µM vitamin C. In an animal model, intra-articular injection of MIA-induced cartilage degradation resembled the pathological changes of OA, and treatment of vitamin C could lessen these changes. Unexpectedly, vitamin C's effects did not strengthen with the increasing dosage, while the 100 mg/kg dosage was more efficient than the 200 or 300 mg/kg dosages. Vitamin C possessed multiple capacities for prevention of OA progress, including a decrease in apoptosis and in the expression of pro-inflammatory cytokines and MMPs in addition to the well-known antioxidation.


Asunto(s)
Ácido Ascórbico/farmacología , Condrocitos/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Vitaminas/farmacología , Animales , Apoptosis , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Humanos , Ácido Yodoacético/toxicidad , Masculino , Metaloproteinasas de la Matriz/metabolismo , Osteoartritis/etiología , Osteoartritis/metabolismo , Estrés Oxidativo , Proteoglicanos/metabolismo , Ratas , Ratas Wistar , Vitaminas/administración & dosificación , Vitaminas/uso terapéutico
16.
Int J Biochem Cell Biol ; 79: 327-336, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27592447

RESUMEN

Arsenic trioxide is used to treat a variety of leukaemia types and causes tumour cell death. However, it is not well known whether arsenic trioxide is toxic to bone osteoblast cells, the precursor cells from which leukaemia cells originate. The aim of this study was to examine the response of osteosarcoma cell line MG63 and primary cultured osteoblasts to arsenic trioxide treatment. After 24h of treatment, arsenic trioxide was more effective at inhibiting cell growth and increasing oxidative stress and DNA damage in MG63 cells than in osteoblasts. In addition, arsenic trioxide arrested cell cycle progression in the G2/M phase, and induced apoptosis in MG63 cells, but not in primary cultured osteoblasts. The results further showed that the expression of transcription factor Nrf2 and its downstream antioxidant effectors, including hemeoxygenase-1, glutathione, and superoxide dismutase, was increased in primary cultured osteoblasts. Additionally, expression of heat shock proteins was also increased. Experiments using inhibitors of antioxidant enzymes in the presence of arsenic trioxide-treated osteoblasts demonstrated that glutathione and superoxide dismutase were responsible for reducing oxidative stress, caspase-3 activity, and apoptosis and that heat shock proteins helped reduce caspase-3 activity. Unexpectedly, there was no apparent effect of the markedly increased hemeoxygenase-1, suggesting that other functions might exist for hemeoxygenase-1. These findings demonstrate that osteosarcoma cells are more sensitive to arsenic trioxide treatment than primary cultured osteoblasts and that primary cultured osteoblasts activate the Nrf2 signalling pathway in response to arsenic trioxide exposure to escape from oxidative damage and apoptosis.


Asunto(s)
Antineoplásicos/efectos adversos , Arsenicales/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismo , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Óxidos/efectos adversos , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Humanos , Osteoblastos/metabolismo , Estrés Oxidativo/efectos de los fármacos
17.
J Dermatol Sci ; 78(3): 206-14, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25840641

RESUMEN

BACKGROUND: IL-9 and its receptor play important roles in the pathogenesis of asthma. Its role in atopic dermatitis (AD) was examined in just a few studies, including nucleotide polymorphisms, increased transcriptional levels of IL-9 and IL-9R in diseased skin, and an association of blood IL-9 levels with clinical severity. OBJECTIVE: Little was known about the pathophysiological regulation of IL-9/IL-9R in AD skin. We asked whether IL-9R was expressed in epidermal keratinocytes; if so, what the functional outcome, cytokine production, and signaling pathway of IL-9/IL-9R in keratinocytes are. METHODS: We measured and compared the expression of IL-9R in skin from AD patients and controls by immunofluorescence. We also performed in vitro studies on the IL-9-treated primary keratinocytes, including flow cytometry for IL-9R expressions, Western blotting for mTOR, S6K, ERK, p38, and STAT3 activations, ELISA for cytokine levels, and immunofluorescence for STIM1. RESULTS: We found that IL-9R was indeed expressed in keratinocytes but not in fibroblasts. Its expression in keratinocytes was enhanced by IL-4 but not by TGF-beta1. IL-9 induced a moderate production of IL-8 but not CXCL16, CCL22, TSLP, nor IL-33. IL-9 induced formation of STIM1-puncta. IL-9 induced ERK phosphorylation both dose- and time-dependently, but not mTOR, S6K, p38, or STAT3. Pretreatment with U0126 (ERK inhibitor) but not rapamycin (mTOR inhibitor) abrogated the IL-9-mediated IL-8 production. Blockage of STIM1 with BTP2 or SKF96265 abrogated ERK phosphorylation and IL-8 production induced by IL-9. CONCLUSION: This study represents the first to show the regulation of the IL-9-STIM1-ERK-IL-8 axis in keratinocyte, and how the axis might play an important role in the pathophysiology of AD.


Asunto(s)
Dermatitis Atópica/etiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-8/biosíntesis , Interleucina-9/farmacología , Queratinocitos/metabolismo , Proteínas de la Membrana/fisiología , Proteínas de Neoplasias/fisiología , Receptores de Interleucina-9/fisiología , Animales , Células Cultivadas , Células Epidérmicas , Femenino , Humanos , Interleucina-4/farmacología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Molécula de Interacción Estromal 1
18.
Chem Biol Interact ; 227: 96-103, 2015 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-25559853

RESUMEN

Arsenic remains an important environmental hazard that causes several human cancers. Arsenic-induced Bowen's disease (As-BD), a skin carcinoma in situ, is the most common arsenical cancer. While great strides have been made in our understanding of arsenic carcinogenesis, how host immunity contributes to this process remains unknown. Patients with As-BD have an impaired contact hypersensitivity response. Although impaired T cell activation has been well-documented in arsenical cancers, how dendritic cell (DC), the key cell regulating innate immunity, regulates the immune response in arsenical cancers remains unclear. Using myeloid derived DC (MDDC) from patients with As-BD and normal controls as well as bone marrow derived DC (BMDC) from mice fed with or without arsenic, we measured the migration of DC. As-BD patients showed an impaired CCL21-mediated MDDC migration in vitro. Arsenic-fed mice had defective DC migration toward popliteal lymph nodes when injected with allogenic BMDCs via foot pad. Using skin from As-BD and normal controls, we found an increased expression of STAT3, a transcriptional factor contributing to impaired DC activation. Arsenic induced STAT3 activation and the production of VEGF in keratinocytes. The increase in VEGF was blocked by inhibiting STAT3 with RNA interference or pharmaceutically with JSI-124. While VEGF by itself minimally induced the expression of CD86 and MHC-II in MDDC, arsenic induced-MDDC activation was abolished by VEGF pretreatment. We concluded that the STAT3-VEGF axis in keratinocytes inhibits DC migration in the microenvironment of As-BD, indicating that cellular interactions play an important role in regulating the disease course of arsenical cancers.


Asunto(s)
Arsénico/toxicidad , Células Dendríticas/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Intoxicación por Arsénico , Células de la Médula Ósea/citología , Enfermedad de Bowen/metabolismo , Enfermedad de Bowen/patología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL21/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Células Mieloides/citología , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Triterpenos/farmacología
19.
ScientificWorldJournal ; 2014: 567148, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24971383

RESUMEN

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. Epirubicin can induce intracellular reactive oxygen species and is widely used to treat unresectable HCC. Progesterone has been found to inhibit the proliferation of hepatoma cells. This study was designed to test the combined effects of epirubicin and progesterone on human hepatoma cell line, HA22T/VGH. These cells were treated with different concentrations of epirubicin with or without the coaddition of 30 µM progesterone and then analyzed for apoptosis, autophagy, and expressions of apoptotic-related proteins and multidrug-resistant gene. Epirubicin treatment dose-dependently inhibited the growth of HA22T/VGH cells. Addition of 30 µM progesterone, which was inactive alone, augmented the effect of epirubicin on the inhibition of growth of HA22T/VGH cells. Cotreatment with progesterone enhanced epirubicin-induced apoptosis, as evidenced by greater increase in caspase-3 activity and in the ratio of the apoptosis-regulating protein, Bax/Bcl-X(L). The combination also caused a decrease in autophagy and in the expression of multidrug resistance-related protein 1 mRNA compared to epirubicin alone. This study shows the epirubicin/progesterone combination was more effective in increasing apoptosis and inversely decreasing autophagy on HA22T/VGH cells treated with epirubicin alone, suggesting that this combination can potentially be used to treat HCC.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Epirrubicina/farmacología , Neoplasias Hepáticas/metabolismo , Progesterona/metabolismo , Apoptosis/genética , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Progesterona/farmacología , ARN Mensajero/genética
20.
J Surg Res ; 188(2): 432-41, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24594218

RESUMEN

BACKGROUND: Although epirubicin, an anthracycline drug, is widely used to treat hepatocellular carcinoma, its therapeutic efficacy is disappointing. Thus, the efficacy of epirubicin may be improved when combined with other drugs. This study investigated the therapeutic potential of combination of progesterone and epirubicin in the treatment of the human hepatoma cell line HA22T/VGH and the possible mechanisms through which this combination might induce apoptosis. MATERIALS AND METHODS: HA22T/VGH cells were treated without or with 25 µM progesterone and/or 0.5 µM epirubicin and analyzed for oxidative stress, redox status, Fas/FasL expression, caspase activity, and apoptosis. RESULTS: HA22T/VGH cells treated with epirubicin increased the production of reactive oxygen species and nitric oxide, the expression of Fas, FasL, and Fas-associated death domain, and the activities of caspase-8 and caspase-3. Epirubicin treatment also decreased glutathione resulting in the induction of apoptosis. Treatment with progesterone alone increased nitric oxide production, but it did not affect the other parameters. However, when HA22T/VGH cells were treated with progesterone and epirubicin, the effects of epirubicin were enhanced. CONCLUSIONS: Our observations suggest that progesterone enhances the efficacy of epirubicin. The increased efficacy is potentially attributed to progesterone's enhancement of epirubicin-induced oxidative stress, thereby reducing redox status. In addition, progesterone sequentially upregulates Fas/FasL to induce the caspase-8 and caspase-3 pathways, thereby resulting in increased apoptosis. The combination had a greater effect on the induction of HA22T/VGH cell apoptosis and could potentially serve as a more effective treatment for hepatocellular carcinoma than epirubicin alone.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Epirrubicina/uso terapéutico , Proteína Ligando Fas/biosíntesis , Proteína de Dominio de Muerte Asociada a Fas/biosíntesis , Neoplasias Hepáticas/tratamiento farmacológico , Progesterona/uso terapéutico , Progestinas/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Quimioterapia Combinada , Epirrubicina/farmacología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Estrés Oxidativo/efectos de los fármacos , Progesterona/farmacología , Progestinas/farmacología , Receptor fas/metabolismo
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